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      Real‐Time pH‐Dependent Self‐Assembly of Ionisable Lipids from COVID‐19 Vaccines and In Situ Nucleic Acid Complexation

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          Abstract

          Ionisable amino‐lipid is a key component in lipid nanoparticles (LNPs), which plays a crucial role in the encapsulation of RNA molecules, allowing efficient cellular uptake and then releasing RNA from acidic endosomes. Herein, we present direct evidence for the remarkable structural transitions, with decreasing membrane curvature, including from inverse micellar, to inverse hexagonal, to two distinct inverse bicontinuous cubic, and finally to a lamellar phase for the two mainstream COVID‐19 vaccine ionisable ALC‐0315 and SM‐102 lipids, occurring upon gradual acidification as encountered in endosomes. The millisecond kinetic growth of the inverse cubic and hexagonal structures and the evolution of the ordered structural formation upon ionisable lipid‐RNA/DNA complexation are quantitatively revealed by in situ synchrotron radiation time‐resolved small angle X‐ray scattering coupled with rapid flow mixing. We found that the final self‐assembled structural identity, and the formation kinetics, were controlled by the ionisable lipid molecular structure, acidic bulk environment, lipid compositions, and nucleic acid molecular structure/size. The implicated link between the inverse membrane curvature of LNP and LNP endosomal escape helps future optimisation of ionisable lipids and LNP engineering for RNA and gene delivery.

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          Most cited references55

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          Lipid nanoparticles for mRNA delivery

          Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle–mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers and possible administration routes for lipid nanoparticle–mRNA systems. We then consider key points for the clinical translation of lipid nanoparticle–mRNA formulations, including good manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies of lipid nanoparticle–mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technology. Lipid nanoparticle–mRNA formulations have entered the clinic as coronavirus disease 2019 (COVID-19) vaccines, marking an important milestone for mRNA therapeutics. This Review discusses lipid nanoparticle design for mRNA delivery, highlighting key points for clinical translation and preclinical studies of lipid nanoparticle–mRNA therapeutics for various diseases.
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            Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers

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              The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs

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                Author and article information

                Contributors
                Journal
                Angewandte Chemie International Edition
                Angew Chem Int Ed
                Wiley
                1433-7851
                1521-3773
                August 28 2023
                July 19 2023
                August 28 2023
                : 62
                : 35
                Affiliations
                [1 ] School of Science STEM College RMIT University Melbourne Victoria 3000 Australia
                [2 ] Université Paris-Saclay CNRS Institut Galien Paris-Saclay 91400 Orsay France
                [3 ] Extreme Light Infrastructure ERIC Za Radnici 835 25241 Dolni Brezany Czech Republic
                [4 ] ESRF, The European Synchrotron 71 avenue des Martyrs 38043 Grenoble France
                [5 ] Ian Holmes Imaging Center Bio21 Molecular Science & Biotechnology Institute University of Melbourne Parkville Victoria 3052 Australia
                [6 ] Australian Research Council Centre for Cryo-Electron Microscopy of Membrane Proteins The University of Melbourne Melbourne Victoria 3010 Australia
                Article
                10.1002/anie.202304977
                405b03a3-82a3-43a9-91e7-0fc7d5a45577
                © 2023

                http://creativecommons.org/licenses/by-nc-nd/4.0/

                http://creativecommons.org/licenses/by-nc-nd/4.0/

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